There are few effective therapeutic options for metastatic renal cell carcinoma (RCC). Conventional chemotherapeutic agents are ineffective since these tumors are unusually resistant to DNA damage, likely due to an exuberant DNA repair response. Sorafenib, as one of the few available effective therapeutic options for metastatic RCC, has been shown to inhibit cell proliferation by inhibition of tyrosine kinases. We have recently shown that sorafenib inhibits soluble epoxide hydrolase, which catalyzes metabolism of the anti-inflammatory epoxyeicosatrienoic acids. Given previous work demonstrating the anti-apoptotic role of p21 in RCC as a potential mechanism for its drug resistance, we asked whether sorafenib signals through this pathway. We now show that sorafenib markedly decreases p21 levels in several RCC and hepatocellular carcinoma cells. Neither the MEK inhibitor PD98059 nor the sEH inhibitor t-AUCB, which represent known sorafenib-targeted signaling pathways, alter p21 levels, demonstrating that the p21 inhibitory effect of sorafenib is independent of these signaling cascades. In cells treated with doxorubicin to augment p21, sorafenib markedly decreases this protein, and the combinations of paclitaxel or doxorubicin with sorafenib show additive cytotoxicity as a function of the VHL status of the cells, suggesting that lower doses of each agent could be used in the clinical setting. In summary, we show a novel signaling pathway by which sorafenib exerts its salutary effects in RCC; future work will focus on the use of these drug combinations in the context of conventional therapeutics, and novel compounds and protocols targeting p21 in conjunction with sorafenib should be pursued.